Mitochondria Functions Modified by Sulfotransferase 1C2

磺基转移酶 1C2 修饰的线粒体功能

• 批准号: 10230976
• 负责人: ROBERT L BACALLAO
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230976
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Aging; Attenuated; Biochemical; Caring; Cell Death; Cellular Metabolic Process; Cholecalciferol; Cholesterol; Clinical; Complex; Consomic Strain; Data; Down-Regulation; Energy Supply; Event; Experimental Models; FDA approved; Gene Delivery; Generations; Genes; Genetic; Genetic Models; Genetic Screening; Goals; Health Care Costs; Hemorrhage; Hospitalization; Hypotension; Hypoxia; Impairment; Incidence; Injury; Ischemia; Ischemic Preconditioning; Kidney; Kidney Diseases; Label; Mass Spectrum Analysis; Membrane; Membrane Fluidity; Membrane Lipids; Membrane Potentials; Messenger RNA; Mitochondria; Modality; Modeling; Nephrology; Norway; Oxygen saturation measurement; Pathologic; Pathway interactions; Patients; Phosphorylation; Physiological; Physiology; Plasmids; Population; Predisposition; Preventive therapy; Process; Production; Proteins; Proteomics; Rat Strains; Rattus norvegicus; Recommendation; Renal function; Reperfusion Injury; Resistance; Respiration; Rodent; Role; Sepsis; Severities; Structure; Syndrome; Testing; Therapeutic Intervention; Toxin; Water; Work; base; cholesteryl sulfate; cost; curative treatments; experimental study; fluorescence lifetime imaging; free radical oxygen; genetic resistance; genetic strain; hemodynamics; ischemic injury; laurdan; mitochondrial membrane; mortality; novel strategies; novel therapeutics; oxidation; preconditioning; prevent; receptor; respiratory; sulfotransferase; targeted treatment; therapeutic target

Acute kidney injury (AKI) is the most common renal disease requiring hospitalization and is associated with significant mortality. There remains no reliable treatment modality for acute kidney injury. In the setting of ischemia or hypoxic injury, early alterations in mitochondrial structure impair cellular energetics, activate cell death pathways, increase oxygen free radical generation and may influence renal hemodynamics. Different models of naturally or experimentally induced resistance to ischemic injury may help to identify biochemical, cellular and physiological events underlying the injury process and provide potential targets for therapeutic intervention. Our prior work uncovered a unique, unanticipated role for sulfotransferase 1C2 (SULT1C2) in changing mitochondria physiology to confer protection against ischemic injury. Since we found SULT1C2 is highly up-regulated in proteomic screens of mitochondria isolated from ischemia-preconditioned kidneys, we tested whether kidneys transduced with plasmids bearing SULT1C2 are resistant to ischemia preconditioning. The goal of this proposal is to delineate the extent of the contribution that SULT1C2 makes to altered cell metabolism resulting in an ischemia preconditioned state. We will test the hypothesis that the mitochondria adaptation due to ischemia preconditioning is due in part to direct action of sulfotransferase 1C2 on mitochondria function brought about by changing cholesterol sulfate levels in mitochondria membranes. In these studies, we will utilize two different models of resistance to AKI; 1) a genetic model of the Brown Norway rat and Brown Norway derived consomic strains of rats, and 2) a model of experimentally induced ischemic preconditioning. Studies in specific objective 1 will test the hypothesis that sulfotransferase 1C2 changes mitochondria respirome composition and physiology due to changes in membrane lipid organization. These experiments will utilize a proteomic approach of label-free-quantitative mass spectroscopy to identify biochemical similarities in different models of resistance. Specific aim 2 will test the hypothesis that sulfotransferase 1C2 requires mitochondria receptors to convert cholesterol to cholesterol sulfate. Lastly aim 3 will test the hypothesis that inhibition of sulfotransferase 1C2 or down-regulation of sulfotransferase 1C2 markedly attenuates cellular protection against ischemia reperfusion injury. These studies will investigate post- ischemic mitochondria respiratory capacity, mitochondrial polarization, renal hemodynamics and renal function protection. Overall, the proposed studies will help provide an understanding of cytoprotective strategies and identify potential therapeutic targets to manage the severity of AKI.

急性肾损伤（AKI）是最常见的需要住院治疗的肾脏疾病